Over one million new patients will be diagnosed with cancer this year. While traditional treatments have been effective at reducing cancer-related deaths, thousands of patients still die from cancer. One of the reasons that traditional chemotherapeutics have not cured cancer is because they non-specifically attack all rapidly growing cells without regard for the synergy between cancers and their microenvironment - which provides important nutrients, growth signals, and protection to cancer cells. Proteoglycans, composed of core proteins and attached glycosaminoglycan side chains, comprise a large part of the cancer microenvironment and are involved in a variety of cancer-related signaling pathways. It is known that cancer cells over-express certain proteoglycans to grow faster and invade nearby tissue. Thus, we propose the development of a novel proteoglycan-based therapeutic strategy to reduce cancer invasion, angiogenesis, growth and metastasis. Several molecules that we have developed can modify proteoglycan biosynthesis to prevent cancer cells from getting nutrients and spreading through tissue by invasion/metastasis. Additionally, heparin, a glycosaminoglycan which has known anti-invasive and anti-metastatic properties, is used to develop a novel drug delivery vehicle which targets cancers, releases anti-cancer drugs, and prevents cancer invasion/metastasis. Brain cancer is one particularly difficult cancer to treat because of the limited diffusion of drugs across the blood-brain barrier (BBB) and the sensitivity of brain tissue. To effectively treat all cancers, the proposed treatment regime is tested extensively in vitro and in vivo in a series of specific aims. In specific aim 1, several proteoglycan-based drugs are tested to find the most potent anti-tumor agents. These drugs are tested in vitro in angiogenesis and invasion assays to assess which drugs can disrupt cancer-specific proteoglycans from interacting with their targets. In specific aim 2, a novel pH-sensitive bioactive drug delivery vehicle designed to release chemotherapy drugs near the tumor is developed using a library of modified heparins. This vehicle is tested for its ability to specificaly target tumor vasculature, deliver its drug payload, and concurrently inhibit tumor invasion. Specific aim 3 then translates these in vitro results to in vivo experiments where the efficacy of the treatment regime is analyzed prior to clinical studies.